1. Field of the Invention
The present invention relates to pharmaceutical compositions and methods for the treatment of irritable bowel disease (IBD) [also termed: irritable bowel syndrome (IBS)]; more particularly for the treatment of diarrhea-predominant IBD.
2. Description of the Prior Art
Irritable bowel syndrome (IBS), a chronic or recurring gastrointestinal disorder, afflicts as many as 24% of women and 19% of men in the U.S., Europe, Japan, and China. IBS produces abdominal pain or discomfort in its victims and accounts for about one-eighth of primary care and more than one-fourth of gastroenterology practice. IBS has tremendous societal and economic impact since persons with IBS symptoms miss three times as many work days as those without and incur 70% higher health care costs. The American Gastroenterological Association has recently underscored the importance of IBS by issuing both a position statement (American Gastroenterological Association (AGA) Medical Position Statement: Irritable Bowel Syndrome. Gastroenterology 112:2118-2119 (1997)) and a technical review (Drossman D A, Whitehead W E, Camilleri M., xe2x80x9cIrritable bowel syndrome: a technical review for practice guideline developmentxe2x80x9d, Gastroenterology 112:2120-2137 (1997)) on IBS. The description herein of IBS is based chiefly on these documents and on other current literature (such as that reviewed in Snape W J Jr., xe2x80x9cIrritable bowel syndromexe2x80x9d, In: Bockus Gastroenterology, 5th edition (W. S. Haubrich, F. Schoffner, ed.) Philadelphia: W. B. Saunders, pp. 1619-1636 (1995)).
IBS presents itself as abdominal pain accompanied by altered bowel habits. There is no established biological marker for IBS, which appears to result from faulty regulation in both the gastrointestinal and nervous systems. Once clinicians rule out other possible causes of IBS symptoms, they must devise a treatment plan based upon the severity and nature of the symptoms as well as other factors such as the degree of impairment the individual is experiencing in the activities of daily living. At present, treatment options range from education and dietary modification to drug therapy to psychological therapy. Drug and/or psychological therapy is called for in those 30% of IBS patients with moderate or severe symptoms. Given an IBS prevalence of 19% to 24%, IBS sufferers requiring such therapy represent 6-7% of the population at large, or well over 100 million individuals in continual need of such therapy in the U.S., Europe, Japan, and China.
While the symptoms of IBS have a physiological basis, no physiological mechanism unique to IBS has been identified. Rather, the same mechanisms that cause occasional abdominal discomfort in healthy individuals operate to produce the symptoms of IBS. The symptoms of IBS are therefore a product of quantitative differences in the motor reactivity of the intestinal tract, and increased sensitivity to stimuli or spontaneous contractions.
Due to a lack of readily identifiable structural or biochemical abnormalities in this syndrome, the medical community has developed a consensus definition and criteria, known as the Rome criteria, to aid in diagnosis of IBS. According to the Rome criteria, IBS is indicated by abdominal pain or discomfort which is (1) relieved by defecation and/or (2) associated with a change in frequency or consistency of stools, plus two or more of the following: altered stool frequency, altered stool form, altered stool passage, passage of mucus, and bloating or feeling of abdominal distention (Dalton, C. and Drossman, D. A., Am Fam Physician 1997 55(3):875-880). Thus, a hallmark of IBS is abdominal pain that is relieved by defecation, and which is associated with a change in the consistency or frequency of stools. IBS may be diarrhea-predominant, constipation-predominant, or an alternating combination of both.
Persons with IBS exhibit hypersensitivity, particularly hyperalgesia, in response to painful distensions in the small bowel and colon and to normal intestinal function. Furthermore, there are also increased or unusual areas of visceral pain. The abdominal pain is often poorly localized, and may be migratory and/or variable in nature. The pain may be worsened by meals and reduced upon defecation. Furthermore, IBS symptoms, including hyperalgesia, are commonly initiated or exacerbated by stress (Dalton, C. and Drossman, D. A., Am Fam Physician 1997 55(3):875-880).
Women apparently are more often affected than men, and the prevalence of irritable bowel syndrome is lower among the elderly (Camilleri, M. and Choi, M.-G., Aliment Pharmacol Ther 1997 11(1):3-15). It also seems clear that psychological factors, either stress or overt psychological disease, modulate and exacerbate the physiological mechanisms that operate in IBS (Drossman, D. A. et al., Gastroenterology 1988 95:701-708; Gaynes B N, Drossman D A: The role of psychosocial factors in irritable bowel syndrome. Baillieres Best Prac Res Clin Gastroenterol 13:437-452, 1999; Jones J, Boorman J, Cann P, Forbes A, Gomborone J, Heaton K, Hungin P, Kumar D, Libby G, Spiller R, Read N, Silk D, Whorwell P: British society of gastroenterology guidelines for the management of the irritable bowel syndrome. Gut 47:ii 1-ii 19, 2000). Some studies suggest that only about 10% to 50% of those afflicted with IBS actually seek medical attention. Nonetheless, IBS still accounts for up to about 3.5 million physician visits per year, and is the most common diagnosis in gastroenterologists"" practice, accounting for about 25% of all patients (Camilleri and Choi, 1997). In a study published in 1993, persons afflicted with IBS were found to have more frequent doctor visits, a lower quality of life, and to miss three times as many days from work as those with no bowel symptoms (Drossman, D. A., Dig Dis Sci 1993 38:1569-1580). As a consequence, persons with IBS incur higher health care costs than those without IBS (Talley, N.J. et al., Gastroenterology 1995 109:1736-1741).
The AGA position statement recommends antispasmodic (anticholinergic) medication for IBS pain and bloating, or a tricyclic antidepressant or serotonin-selective reuptake inhibitor if the pain is severe. Dietary fiber is recommended (cisapride is also mentioned) for IBS constipation, whereas loperamide is recommended for diarrhea. For treatment of IBS patients presented with predominant diarrhea, the bile acid sequestrant xe2x80x9ccholestyramine may be considered for a subgroup of patients with cholecystectomy or who may have idiopathic bile acid malabsorption.xe2x80x9d Clearly, there is no single pharmacologic treatment appropriate to all IBS sufferers. However, it is equally clear that it is acceptable clinical practice to employ a bile acid sequestrant to treat diarrhea associated with IBS.
The technical review issued by the AGA states that treatment with the bile acid sequestrant xe2x80x9ccholestyramine should be considered in patients with IBS who have predominant diarrhea.xe2x80x9d Cholestyramine, a copolymer of styrene and divinylbenzene possessing trimethylbenzylammonium groups, has a somewhat limited capacity to bind bile acids, so very large quantities (as much as 20 grams per day) must be ingested in order to alleviate symptoms.
There is presently no effective treatment for irritable bowel syndrome (K. B. Klein, Controlled treatment trials in the irritable bowel syndrome: a critique, Gastroenterology 95: 232-241, 1988). Although largely ineffective, current treatment is multifactorial and consists of stress management, diet, and drugs, in that order. The patient is reassured that the disease is not life threatening and is advised to reduce or eliminate any controllable stress in his or her life. Relaxation exercises and biofeedback may be attempted to alter the psychogenic components of the illness. With respect to diet, the patient is advised to avoid any food to which he or she possesses a known sensitivity with respect to exacerbating the problem. A high fiber diet, either insoluble wheat bran or soluble psyllium, is almost routinely recommended, but with little if any positive benefit (Dietary fiber, food intolerance, and irritable bowel syndrome, Nutrition Reviews 48: 343-346, 1990).
Numerous drugs have been tried for the treatment of irritable bowel syndrome, but none has demonstrated sufficient efficacy to be of practical benefit to most patients. Psychoactive drugs, such as anxiolytics and antidepressants, even if effective for a given patient, have very limited, short-term utility because of the high potential for addiction to and abuse of these agents. Antispasmodics and various antidiarrheal preparations have been used but, even if they are effective, long-term treatment is precluded by problems such as development of tolerance, toxicity, or abuse potential. Several excellent reviews examine in detail the symptomology, diagnosis, and treatment of irritable bowel syndrome. These include: W. L. Hasler and C. Owyang, Irritable bowel syndrome, In: Textbook of Gastroenterology, Ed. by T. Yamada, J. B. Lippincott Company, Philadelphia, Pa., 1696-1714 (1991); M. M. Schuster, Irritable bowel syndrome, In: Gastrointestinal Disease, Pathophysiology Diagnosis and Management, Fourth Edition, Ed. by M. H. Sleisenger, J. S. Fordtran, W. B. Saunders Company, Philadelphia, Pa., 1402-1418 (1989); W. S. Haubrich, Irritable bowel syndrome, Gastroenterology, Fourth Edition, Ed. by J. E. Berk, W. B. Saunders Company, Philadelphia, Pa., 2425-2444 (1985) and Jones J, Boorman J, Cann P, Forbes A, Gomborone J, Heaton K, Hungin P, Kumar D, Libby G, Spiller R, Read N, Silk D, Whorwell P: British society of gastroenterology guidelines for the management of the irritable bowel syndrome. Gut 47:ii 1-ii 19, (2000).
Numerous patents have claimed activities of various types represented as being effective for relieving irritable bowel syndrome symptoms. For the most part they relate to substances which possess spasmolytic activity and thereby decrease intestinal motility. U.S. Pat. Nos. 4,611,011, 4,701,457, and 4,745,131 disclose a series of amidinoureas which reduce intestinal motility and are useful for treating irritable bowel syndrome. 1-Azabicyclo[2.2.2]octan-3-yl-2-aryl-3-azacyclo-2-hydroxypropionates and their quaternary salts, which possess antispasmodic activity and are useful for treating irritable bowel syndrome, are disclosed in U.S. Pat. No. 4,843,074. Calcium channel antagonists exhibit muscle relaxing and antispasmodic activities. A series of substituted imidazolyl-alkyl-piperazine and diazepine derivatives, disclosed in U.S. Pat. No. 5,043,447, are calcium channel antagonists and may be useful as antispasmodics for treating irritable bowel syndrome. 2-Aminomethylalkynylalkyl-1,3-dithiane derivatives with calcium-channel blocking activity and potentially similar uses are disclosed in U.S. Pat. No. 4,877,779. A series of triazinone derivatives with spasmolytic activity for treating irritable bowel syndrome are disclosed in U.S. Pat. No. 4,562,188.
In addition to antispasmodic agents, compounds with other activities have been disclosed which may relieve the symptoms of irritable bowel syndrome. U.S. Pat. No. 4,239,768 discloses a series of arylimidazolidinylidene ureas which decrease the sensitivity of the bowel to distension and thereby relieve irritable bowel symptoms. U.S. Pat. No. 4,970,207 discloses a series of benzodiazepine derivatives which are cholecystokinin antagonists and which may be useful for a large number of medical indications which include irritable bowel syndrome.
Since diarrhea is one frequent component of irritable bowel symptomatology, anti-diarrheal agents have been used to treat this disease. Unfortunately, such agents tend to exacerbate the constipatory phase of the disease and are, therefore, of little practical, long-term benefit.
Attempts to treat IBS generally focus on either (1) treatments directed to the intestinal tract (so-called xe2x80x9cend organ therapyxe2x80x9d) or (2) treatments directed to affective disorders mediated by the CNS which are associated with IBS (Farthing, M. J. G., Drugs 1998 56(1): 11-21). Among the former are gut transit accelerants, such as wheat bran, soluble fiber, and polycarbophil calcium, for constipation-predominant IBS; antidiarrheals, such as loperamide, diphenoxylate, and codeine phosphate, for diarrhea-predominant IBS; and anticholinergics and smooth muscle relaxants, such as cimetropium bromide, pinaverium bromide, octilium bromide, trimebutine, and mebeverine, for diarrhea-predominant IBS and abdominal pain. In addition, alterations in diet have been targeted for those patients with food sensitivities or food allergies.
The end organ therapy treatments for IBS have proved ineffective or contain inherent drawbacks that limit their usefulness. For example, while the gut accelerants are useful to accelerate gut transit, they also exacerbate abdominal pain and bloating. Likewise, while antidiarrheals, such as loperamide, are often effective in treating diarrhea-predominant IBS, they are ineffective in treating the additional symptoms associated with IBS, such as abdominal pain. As a consequence, end organ therapy often is limited to patients with mild or moderate symptoms.
The anticholinergics and smooth muscle relaxants are effective in relieving pain associated with IBS, although their effects on other symptoms associated with IBS is unclear (Committee, Gastroenterology 1997 112:2120-2137; Pace, F. et al., Digestion 1995 56:433-442). In addition, some of the most effective compounds in these classes are not available for use in the United States, since they have not been approved by the Federal Food and Drug Administration (Committee, 1997). Finally, dietary alterations are of limited utility for a small segment of IBS patients.
Central nervous system treatments have received attention as potential IBS therapies because of the well recognized link between affective disorders and IBS, and also because of the disturbances in bowel health that occurs in individuals with these disorders. The tricyclic antidepressants, such as amitriptyline, imipramine, and doxepin, are frequently used to treat IBS, due to the neuromodulatory and analgesic properties of these compounds, which are independent of their psychotropic effects. However, because of their psychotropic properties, administration of these drugs requires long-term care, and are usually only given to patients with severe or refractory symptoms, impaired daily function, and associated depression or anxiety attacks. Furthermore, the newer antidepressants, in particular the specific serotonin reuptake inhibitors, such as fluoxetine, serraline, and paroxetine, have not been shown to be more effective than the tricyclic antidepressants, although some anecdotal evidence suggests these compounds may have fewer side effects (Committee, 1997).
Nalmefene glucuronide, an opioid receptor antagonist, has been investigated as a treatment for constipation-predominant IBS (Chami, T. N., et al., Am J Gastroenterol 1993 88:1568 [abstract]). Over an eight-week period, eight patients received 16 mg nalmefene glucuronide three times a week. While the patients reported decreased transit time and increased stool frequency, nalmefene glucuronide did not reduce abdominal pain or bloating, and stool consistency was not improved. The present inventors believe that the failure of nalmefene to treat pain associated with IBS can be attributed to the fact that this study used a high dose of nalmefene which antagonizes both excitatory and inhibitory opioid receptor-mediated functions in the gut as well as in the CNS. This view is supported by recent evidence that 1,000-fold lower doses of nalmefene (ca. 15:g, IV) have been shown to markedly enhance morphine""s analgesic potency (Joshi et al., Anesthesiol. 1999, 90(4): 1007-11), whereas doses of  greater than 0.5 mg markedly attenuate opioid analgesia (Konieczko, K. M. et al., Br J Anaesth 1988 61(3):318-23).
Recent reports of successful treatment of IBS patients with high doses of the kappa opioid agonist, fedotizine (30 mg, three times daily) (Dapoigny, M. et al., Dig Dis Sci 1995 40(10):2244-9; Gue, M. et al., Gastroenterology 1994 107(5):1327-34) may be due to masking of supersensitized excitatory opioid receptor activity in the gut by activation of inhibitory opioid receptor functions, analogous to methadone maintenance of opioid addicts. Supersensitized excitatory opioid receptor functions in the gut may also result in tolerance to the analgesic effects of endogenous opioids (Wang, L. and Gintzler, A. R., J Neurochem 1995 64(3):1102-6), which could account for the abnormal visceral pain associated with IBS.
U.S. Pat. No. 5,512,578 discloses that the analgesic potency of bimodally-acting opioid agonists can be enhanced, and the tolerance/dependence liability reduced, upon coadministration of ultralow doses of selective excitatory opioid receptor antagonists. As used herein, xe2x80x9cexcitatory opioid receptor antagonistsxe2x80x9d are compounds that bind to and inactivate excitatory opioid receptors, but not inhibitory opioid receptors, on neurons in the nociceptive pathways. Such selective excitatory opioid receptor antagonists include, when administered at appropriately low doses, naloxone, naltrexone, etorphine, and dihydroetorphine. The selective excitatory opioid receptor antagonists attenuate excitatory, but not inhibitory, opioid receptor functions in nociceptive (pain) pathways of the peripheral and central nervous systems. As a result, symptoms associated with activation of excitatory opioid receptors, such as anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects, are blocked, whereas the analgesic effects of bimodally acting opioid agonists, which are mediated by the inhibitory opioid receptors, are unmasked and thereby enhanced (see Crain, S. M. and Shen, K.-F., Proc Natl Acad Sci U S A 1995 92:10540-10544; Crain, S. M. and Shen, K.-F., Trends Pharmacol Sci 1998 19:358-365; Ann N Y Acad Sci 1998 845:106-25; Shen, K.-F. and Crain, S. M., Brain Res 1997 757(2):176-90). The predictions based on these preclinical studies have been recently confirmed by clinical studies on postsurgical patients which demonstrated that cotreatment with morphine plus low-dose naloxone or nalmefene markedly enhanced the analgesic potency of morphine administered over 24-hour test periods (Joshi et al., Anesthesiol. 1999, 90(4): 1007-11; Gan, T. J. et al., Anesthesiol. 1997 87:1075-1081).
U.S. Pat. No. 5,512,578 further discloses that ultralow doses of naltrexone can, alone or in combination with low-dose methadone, provide effective longterm maintenance treatment for opioid addiction to prevent relapse to drug abuse. Furthermore, ultralow doses of selective excitatory opioid receptor antagonists can be administered alone to chronic pain patients to enhance the analgesic potency and reduce the tolerance/dependence liability of endogenous opioid peptides, such as enkephalins, dynorphins, and endorphins, which are elevated in chronic pain patients (Crain and Shen, 1995). However, there is no teaching or suggestion in U.S. Pat. No. 5,512,578 that administration of a selective excitatory opioid receptor antagonist would be useful in treating symptoms of IBS. In particular, there is no teaching or suggestion that administration of a selective excitatory opioid receptor antagonist would be useful in treating symptoms of IBS that are unrelated to the nociceptive pathways, such as stool frequency or consistency.
U.S. Pat. No. 5,472,943 also discloses a method wherein coadministration of an ultralow dose of a selective excitatory opioid receptor antagonist with a bimodally-acting opioid agonist selectively enhances the analgesic effect of the bimodally-acting opioid agonist while reducing the undesirable side-effects associated with longterm administration of the opioid agonist. However, U.S. Pat. No. 5,472,943 does not disclose that a selective excitatory opioid receptor antagonist can be used in the absence of a bimodally-acting opioid agonist.
Both U.S. Pat. Nos. 5,580,876 and 5,767,125 also disclose a method to selectively enhance the analgesic effect of a bimodally-acting opioid agonist while reducing unwanted side-effects associated with the administration of the opioid agonist by coadministration of the opioid agonist with an amount of an excitatory opioid receptor antagonist, such as naltrexone or nalmefene, effective to enhance the analgesic effect of the bimodally-acting opioid agonist while reducing the undesirable side-effects. U.S. Pat. Nos. 5,580,876 and 5,767,125 disclose use of an excitatory opioid receptor antagonist alone for treatment of opioid addicts, and do not teach or suggest that administration of a selective excitatory opioid receptor antagonist would be useful in treating symptoms of IBS. In particular, there is no teaching or suggestion that administration of a selective excitatory opioid receptor antagonist would be useful in treating other symptoms of IBS, such as stool frequency or consistency.
U.S. Pat. No. 5,585,348 relates to a method for reducing hyperalgesia associated with administration of nerve growth factor or related growth factors. The method comprises administration of a selective excitatory opioid receptor antagonist prior to or simultaneously with the administration of nerve growth factor. However, U.S. Pat. No. 5,585,348 does not disclose that the selective opioid receptor antagonist may be administered in the absence of nerve growth factor, and does not teach or suggest that the administration of a selective excitatory opioid receptor antagonist alone would be useful in treating IBS.
In spite of the many treatments and inventions devised to relieve or prevent irritable bowel syndrome, the unfortunate fact is that presently no suitable long term, safe and efficacious treatment or preventative is available for this troublesome and widespread disease.
It is an object of the invention to provide novel pharmaceutical compositions and methods for the long term, safe and efficacious treatment of irritable bowel disease (IBD) or syndrome (IBS).
The above and other objects are realized by the present invention, one embodiment of which relates to a method for treating irritable bowel syndrome in a subject in need of such treatment, comprising administering to the subject an amount of a polyamine effective to treat irritable bowel syndrome in the subject, the polyamine being selected from the group consisting of:
Rxe2x80x94NHxe2x80x94(CH2)axe2x80x94NHxe2x80x94(CH2)bHxe2x80x94(CH2)cxe2x80x94NH2,xe2x80x83xe2x80x831) 
CF3xe2x80x94C6H5xe2x80x94(CH2)axe2x80x94NHxe2x80x94(CH2)bxe2x80x94NHxe2x80x94(CH2)cxe2x80x94NHxe2x80x94(CH2)dxe2x80x94NHxe2x80x94(CH2)exe2x80x94C6H5xe2x80x94CF3,xe2x80x83xe2x80x832) 
Rxe2x80x94NHxe2x80x94(CH2)axe2x80x94NHxe2x80x94C6H6xe2x80x94NHxe2x80x94(CH2)bxe2x80x94NHxe2x80x94R andxe2x80x83xe2x80x833) 
PIPxe2x80x94(CH2)aNHxe2x80x94(CH2)bxe2x80x94NHxe2x80x94(CH2)cxe2x80x94PIP,xe2x80x83xe2x80x834) 
wherein:
R is alkyl, aryl, aralkyl, alkaryl, or cyclo-alkyl having up to about 10 carbon atoms, and any of the alkyl chains may optionally be interrupted by at least one etheric oxygen atom,
PIP is piperidine and
a, b, c, d, and e may be the same or different and are integers from 1-10.
Another embodiment of the invention concerns a pharmaceutical composition adapted for administration to a subject suffering from irritable bowel syndrome comprising a therapeutically effective amount of a polyamine as described above to treat irritable bowel syndrome and a pharmaceutically acceptable carrier therefor.
A still further embodiment of the invention comprises an article of manufacture comprising packaging material and a pharmaceutical agent contained within the packaging material, wherein the pharmaceutical agent is effective for the treatment of a subject suffering from irritable bowel syndrome, and wherein the packaging material comprises a label which indicates that the pharmaceutical agent can be used for ameliorating the symptoms associated with irritable bowel syndrome, and wherein the pharmaceutical agent is selected from the group consisting of polyamines having the formula:
Rxe2x80x94NHxe2x80x94(CH2)axe2x80x94NHxe2x80x94(CH2)bHxe2x80x94(CH2)cxe2x80x94NH2,xe2x80x83xe2x80x831) 
xe2x80x83CF3xe2x80x94C6H5xe2x80x94(CH2)axe2x80x94NHxe2x80x94(CH2)bxe2x80x94NHxe2x80x94(CH2)cxe2x80x94NHxe2x80x94(CH2)dxe2x80x94NHxe2x80x94(CH2)exe2x80x94C6H5xe2x80x94CF3,xe2x80x83xe2x80x832)
Rxe2x80x94NHxe2x80x94(CH2)axe2x80x94NHxe2x80x94C6H6xe2x80x94NHxe2x80x94(CH2)bxe2x80x94NHxe2x80x94R andxe2x80x83xe2x80x833) 
PIPxe2x80x94(CH2)aNHxe2x80x94(CH2)bxe2x80x94NHxe2x80x94(CH2)cxe2x80x94PIP,xe2x80x83xe2x80x834) 
wherein:
R is alkyl, aryl, aralkyl, alkaryl, or cyclo-alkyl having up to about 10 carbon atoms, and any of said alkyl chains may optionally be interrupted by at least one etheric oxygen atom,
PIP is piperidine and
a, b, c, d, and e may be the same or different and are integers from 1-10.